Diabetes is the most significant co-morbidity of patients with heart failure (HF), which adversely affects outcomes in patients with HF and ischemic heart disease. It is characterized by a decreased collateral vessel formation in response to coronary ischemic events. Therefore capillary density and diameter exhibited progressive decreases of more than 20% over 26 week of diabetes. Vascular endothelial growth factor (VEGF) is a major mediator of neovascularization in physiological and pathological conditions with crucial roles in developmental blood vessel formation was found to be inhibited in diabetic complications. Abnormalities of the coronary collateral circulation have been reported in clinical and experimental diabetes mellitus. Our initial and continuing motivation to study of REDOX SIGNALING IN ISCHEMIC REPERFUSED heart leads us to step into a new research field of redox regulation and stress signal in diabetes mellitus. Thioredoxin (Trx) a redox active protein has recently been shown by our laboratory to induce HO-1 and VEGF that protects myocardium from oxidative stress. Trx has angiogenic potential, which may contribute to de novo development of vessels by vasculogenesis or angiogenesis in ischemic/infarcted myocardium. Our long-term goal of this project is to understand the oxidative stress induced abnormalities in diabetic heart failure (HF) and to establish effective therapeutic strategies to treat diabetic patients in future. Thus, this study will attempt to address an important clinical issue by identifying potential candidates of Trx-VEGF signaling in diabetic animals. This study will utilize a broad multidisciplinary approach that will combine various techniques, modern molecular biology, imaging technology, gene therapy, gene targeting and physiology. Aim I. The impact of oxidative stress/redox status with increased diabetic condition will be studied along with caveolin, Trx, HO-1 and VEGF expression and angiogenesis. Aim II. Overexpression of Thiredoxin-1 involves increased HO-1, VEGF/VEGFR2 and eNOS expression followed by increased neovascularization. Aim III. Involvement of GSK-3 beta and beta-catenin mediated VEGF signaling in diabetic animals will be explored related to angiogenesis. Aim IV. Combination gene therapy with Ad-VEGF and Ad-Ang- 1 triggers survival signal and neovascularization. Thoughtfully designed series of experiments in streptozotocin-induced diabetic rat and genetically engineered mouse model will be used. Collectively, the proposed study will contribute to our understanding of the mechanisms that regulate angiogenesis in association with diabetic-related disorders, and may provide novel therapeutic treatment strategies to cure ischemic disease.